WO2020168963A1

WO2020168963A1 - Substituted fused aromatic ring derivative, composition and use thereof

Info

Publication number: WO2020168963A1
Application number: PCT/CN2020/074983
Authority: WO
Inventors: 王义汉; 邢青峰; 艾义新
Original assignee: 深圳市塔吉瑞生物医药有限公司
Priority date: 2019-02-18
Filing date: 2020-02-13
Publication date: 2020-08-27
Also published as: JP7323218B2; US20220098204A1; EP3904355A4; CN111574521A; EP3904355A1; JP2022520282A

Abstract

Provided are a substituted fused aromatic ring derivative, a composition containing the compound, and a use thereof. The substituted fused aromatic ring derivative is a compound represented by formula (I) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof. The compound and the composition can be used to treat various protein tyrosine kinase-mediated diseases or disorders.

Description

Substituted aromatic condensed ring derivative and its composition and use

Cross references to related applications

This application claims the priority of the Chinese invention patent application 201910127767.3 filed on February 18, 2019. The entire content of the application is incorporated by reference as part of this application.

Technical field

The present invention belongs to the technical field of medicine, and particularly relates to substituted aromatic fused ring derivatives with inhibitory effect on protein tyrosine kinases, pharmaceutical compositions containing them, and their preparation methods and uses.

Background technique

Protein kinases (PKs) are enzymes that catalyze the phosphorylation of specific serine, threonine or tyrosine in cellular proteins. The post-translational modifications of these substrate proteins act as molecular switches that play a key role in various biological processes, such as controlling cell growth, metabolism, tumor microenvironment (for example, VEGFR), differentiation, and apoptosis. Abnormal, excessive or generally unsuitable PK activity has been observed in several disease states, including malignant proliferative diseases, such as medullary thyroid carcinoma (MTC) and other human malignancies, functional mutations, acute myeloid leukemia (AML) ITD (Internal Cohesive Repeat)-mutation in FLT3, c-Kit mutation of gastrointestinal stromal tumor (GIST) and RET of BCR-ABL rearrangement of chronic myelogenous leukemia (CML). In addition, the activation and/or overexpression of tyrosine kinases (such as TrkA, TrkB, TrkC, and RET) cause cancer. Many tyrosine kinases are homologous to each other: inhibiting one tyrosine kinase can also produce a certain inhibitory activity against other tyrosine kinases. For example, imatinib has been used as a therapeutic agent not only for CML patients (based on inhibiting BCR-ABL kinase), but also for GIST cancer patients (based on inhibiting c-Kit kinase). The following briefly describes several targets used in cancer therapy and the issues involved.

RET

RET (Rearranged during transfection) belongs to the family of receptor tyrosine kinase proteins and is a cell surface molecule that signals cell growth and differentiation. RET gene mutation or RET gene fusion has been identified as a driving factor for certain cancers. The incidence of RET gene fusion in non-small cell lung cancer is about 2%, and the incidence in Papillary Thyroid Cancers (PTCs) is 10% to 20%. The most common fusion partners include KIF5B, TRIM33, CCDC6 and NCOA4. The incidence of RET gene mutation in medullary thyroid cancer (Medullary Thyroid Cancers, MTCs) is about 60%, and the most common mutation site is M918T. RET inhibitor resistance mutations include but are not limited to amino acid position 804 (V804M, V804L, V804E), amino acid position 805 (E805K), and amino acid position 806 (Y806C, Y806E).

TRK

Trk (Tropomyosin-related kinase, tropomyosin-related kinase) is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophic factors (NT). The Trk receptor family has 3 members, namely TrkA, TrkB and TrkC. Neurotrophic factors include (1) nerve growth factor (NGF) that can activate TrkA, (2) brain-derived neurotrophic factor (BDNF) and NT4/5 that can activate TrkB, and (3) NT3 that can activate TrkC. Trk is widely expressed in neuronal tissues and is related to the maintenance, signal transduction and survival of neuronal cells. The literature also shows that Trk overexpression, activation, amplification and/or mutation are associated with many cancers, including neuroblastoma, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, multiple myeloma, and astrocytoma And medulloblastoma, glioma, melanoma, thyroid cancer, pancreatic cancer, large cell neuroendocrine tumor and colorectal cancer. In addition, inhibitors of the Trk/neurotrophic factor pathway have been shown to be effective in the treatment of various preclinical animal models of pain and inflammatory diseases.

FLT3

FLT3 (FMS-like tyrosine kinase 3, FMS-like tyrosine kinase 3) belongs to the kinase protein of the class III receptor tyrosine kinase family. FLT3 is a receptor tyrosine kinase that plays a role in regulating normal blood cell production and is overexpressed in leukemic embryonic cells. Mutations in the FLT3 gene are characterized by 30% of AML cases. Convergent duplication (ITD) mutations in FLT3 (accounting for approximately 23% of AML cases) are associated with a particularly poor prognosis. The prognostic implications of the FLT3/D835 point mutation found in approximately 7% of cases at the time of diagnosis have not been established. Inhibition of FLT3 and its mutations may be advantageous.

c-Kit

c-KIT (also known as CD117) is a type of transmembrane receptor protein with tyrosine kinase activity encoded by the retroviral proto-oncogene c-kit. c-KIT kinase is composed of extracellular domain, transmembrane domain and intracellular domain. The c-KIT ligand is a stem cell factor (SCF), which binds to the extracellular domain of c-KIT to induce receptor dimerization and activate downstream signal transduction pathways. The c-KIT mutation usually occurs in the DNA (exon 11) that encodes the domain of the membrane region. They also appear in exons 7, 8, 9, 13, 14, 17, and 18 at a lower frequency. The mutation makes c-KIT function independent of activation by SCF, resulting in a high cell division rate and possible genome instability. The mutation of c-KIT has been implicated in the pathogenesis of several diseases and conditions, including systemic mastocytosis (SM), gastrointestinal stromal tumors (GIST), acute myeloid leukemia (Acute Myeloid) Myelocytic) Leukemia, AML), melanoma and seminoma. Therefore, there is a need to develop therapeutic agents that inhibit c-KIT, and particularly drugs that inhibit mutant c-KIT.

PDGFR

PDGFR (Platelet Derived Growth Factor Receptor, platelet-derived growth factor receptor) is a cell surface tyrosine kinase receptor of a member of the platelet-derived growth factor (PDGF) family. PDGF subunits PDGFα and PDGFβ are important factors that regulate cell proliferation, cell differentiation, cell growth, development and many diseases including cancer. The PDGFRαD842V mutation has been found in a different subset of gastrointestinal stromal tumors (GIST), usually from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance.

VEGFR

VEGFR (Vascular Endothelial Growth Factor, vascular endothelial growth factor) is an important signal transduction protein involved in angiogenesis and angiogenesis. As a hint of its name, VEGFR activity is mainly limited to vascular endothelial cells, although it has an effect on a limited number of other cell types. In vitro, it has been confirmed that VEGFR stimulates endothelial cell mitogenesis and cell migration. VEGFR also promotes microvascular permeability and is sometimes called a vascular permeability factor. VEGFR kinase has been used as a target for solid tumors, such as highly vascularized malignant tumors such as kidney cancer, glioblastoma, and liver cancer.

Summary of the invention

The present invention provides a novel aromatic condensed ring derivative and a composition containing the compound and uses thereof, which are effective for certain wild-type and mutant RET, KIF5B-RET, CCDC6-RET, TrkA, TrkB, TrkC The kinases of FLT3, c-Kit, PDGFR and VEGFR have better inhibitory activity and selectivity, and have better pharmacodynamics and/or pharmacokinetic properties, which can treat protein kinase-mediated diseases.

In this regard, the present invention adopts the following technical solutions:

In one aspect, the invention relates to compounds of formula (I):

among them,

· Ring A and Ring B form an aromatic fused ring;

·A _{1 is} selected from N atom or C atom, which is optionally substituted by R ₁ ;

· A _{2 is} selected from N atom or C atom, which is optionally substituted by R ₂ ;

Wherein each R ₁ and R ₂ are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxy Group, C _1-6 haloalkoxy or -OC _3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D until fully deuterated;

· A ₃ and A ₄ are each independently selected from C atom or N atom;

· A ₅ and A ₆ are each independently selected from N atoms or C atoms, which are optionally substituted by R;

· A ₇ and A ₈ are each independently selected from N atoms or C atoms, which are optionally substituted by R′;

Wherein R and R'are each independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _3-7 cycloalkyl or -L ₁ -R _a ; wherein the above-mentioned groups are optionally substituted by one or more D until fully deuterated;

Wherein, L ₁ is selected from a bond, O, or NH; R _a is selected from phenyl or containing 1-3 N, 5 to 6 membered heteromonocyclyl aryl, O or S heteroatoms, wherein said group is optionally substituted with one Or replaced by multiple R _b ;

· B ₁ , B ₂ , B ₃ and B ₄ are each independently selected from CR ^* or N;

Wherein each R ^{* is} independently selected from H, D, halogen, -CN, -R _c , -C (O) R _c , -C (O) OR _c , -C (O) NR _c R _d ,- NR _c R _d , -NR _c C(O)R _c , -NR _c C(O)OR _c , -NR _c C(O)NR _c R _d , -OR _c , -OC(O)R _c ,- OC(O)OR _c or -OC(O)NR _c R _d ;

· L ₂ and L ₃ are each independently selected from bond, NH, CH ₂ , CHD or CD ₂ ;

· Ring C is selected from a phenyl group or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms, wherein the group is optionally substituted by one or more R _b' ;

Wherein each of R _b and R _{b 'are} each independently selected from _{H, D, -OH, -NH 2} , _{halogen, -CN, -R c, -C (} O) R c, -C (O) OR c , -C(O)NR _c R _d , -NR _c R _d , -NR _c C(O)R _c , -NR _c C(O)OR _c , -NR _c C(O)NR _c R _d ,- OR _c , -OC(O)R _c , -OC(O)OR _c or -OC(O)NR _c R _d , or two R _b groups or two R _b on the same atom or adjacent atoms _' Groups can be taken together to form a C _3-7 cycloalkyl, a 3 to 7 membered heterocyclic group, a C _6-10 aryl group or a 5 to 10 membered heteroaryl group optionally substituted with one or more R _e ;

Each R _c and R _{d is} independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C _6-10 aryl group or 5 to 10-membered heteroaryl group, or R _c and _Rd together with the N atom to which they are attached form a 3 to 7-membered heterocyclic group or 5 to 10-membered heteroaryl group Group; wherein the group is optionally substituted by one or more R _e ;

Each R _e is independently selected from _{H, D, -OH, -NH 2} , _{halogen, -CN, -R f, -C (} O) R f, -C (O) OR f, -C (O) NR _f R _g , -NR _f R _g , -NR _f C(O)R _f , -NR _f C(O)OR _f , -NR _f C(O)NR _f R _g , -OR _f , -OC( _{O) R f, -OC (O} ) oR f , or _{_{-OC (O) NR f R g}} , or the same atom or two adjacent groups R _e on the atom may together form a C _3-7 cycloalkyl group, 3-7 yuan heterocyclyl, C _6-10 aryl group or 5 to 10 membered heteroaryl; wherein each of R ^e defined group is optionally substituted by one or more D, until fully deuterated;

Each R _f and R _{g is} independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C _6-10 aryl group or 5 to 10-membered heteroaryl group, or R _f and R _g together with the N atom to which they are attached form a 3 to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group Group; wherein each group in the definition of R _f and R _g is optionally substituted by one or more D until fully deuterated;

Or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

In another aspect, the present invention provides a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient. In specific embodiments, the compounds of the invention are provided in a therapeutically effective amount. In a specific embodiment, the compound of the invention is provided in a prophylactically effective amount.

In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition of the present invention is used to treat diseases mediated by protein kinases. Use in medicine.

In another aspect, the present invention provides a method for treating a disease in a subject, such as a protein kinase-mediated disease, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof, Hydrate or solvate, or the pharmaceutical composition of the present invention.

In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention, for use in the treatment of diseases, such as protein kinase-mediated diseases.

In a specific embodiment, the disease is mediated by at least one wild-type or mutant RET, KIF5B-RET, CCDC6-RET, Trk, FLT3, c-Kit, PDGFR or VEGFR kinase. In a specific embodiment, the mutants RET, KIF5B-RET and CCDC6-RET are selected from V804L, V804M, V804E, M918T, E805K, Y806C, Y806E, C634Y or C634W. In a specific embodiment, the Trk kinase is selected from Trk A, TrkB or TrkC; in a specific embodiment, the mutant TrkA is selected from G595R. In a specific embodiment, the mutant FLT3 is selected from F691L, D835Y, D835V, D835H, D835F, D835E, Y842C, Y842D, Y842H, Y842N, or Y842S; in a specific embodiment, the mutant FLT3 is selected from FLT3-ITD mutation. In a specific embodiment, the mutant c-Kit is selected from D816V, D816Y, D816F, D816K, D816A or D816G. In a specific embodiment, the mutant PDGFR is selected from D842V.

From the following specific embodiments, examples and claims, other objects and advantages of the present invention will be apparent to those skilled in the art.

definition

Chemical definition

The definitions of specific functional groups and chemical terms are described in more detail below.

When listing numerical ranges, it is intended to include each value and sub-ranges within the stated range. For example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1 -2} , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C _{5 -6} alkyl.

The "C _1-6 alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and is also referred to herein as a "lower alkyl group". In some embodiments, C _1-4 alkyl is particularly preferred. Examples of the alkyl group include but are not limited to: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert Butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-amyl (C ₅ ) and n-hexyl (C ₆ ). Regardless of whether or not the alkyl group is modified with "substituted", each of the alkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. The appropriate substituents are as follows definition.

"C _2-6 alkenyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds (for example, 1, 2 or 3 carbon-carbon double bonds) . One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, C _2-4 alkenyl is particularly preferred. Examples of the alkenyl group include but are not limited to: vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butene Group (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), etc. Regardless of whether the alkenyl group is modified with "substituted" in front of it, each of the alkenyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are as follows definition.

"C _2-6 alkynyl" means having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (for example, 1, 2 or 3 carbon-carbon triple bonds), and optionally one or more carbon atoms -A straight or branched hydrocarbon group with carbon double bonds (for example, 1, 2 or 3 carbon-carbon double bonds). In some embodiments, C _2-4 alkynyl is particularly preferred. In some embodiments, the alkynyl group does not contain any double bonds. One or more carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of the alkynyl group include, but are not limited to: ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2- Butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), etc. Regardless of whether the alkynyl group is modified with "substituted" in front of it, each of the alkynyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. Suitable substituents are as follows definition.

"C _1-6 alkoxy" refers to the group -OR, where R is a substituted or unsubstituted C _1-6 alkyl group. In some embodiments, C _1-4 alkoxy is particularly preferred. Specific alkoxy groups include but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, N-hexyloxy and 1,2-dimethylbutoxy.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

Therefore, "C _1-6 haloalkyl" and "C _1-6 haloalkoxy" refer to the above-mentioned "C _1-6 alkyl" and "C _1-6 alkoxy", which are substituted by one or more halogen groups.团 Replacement. In some embodiments, C _1-4 haloalkyl is particularly preferred, and C _1-2 haloalkyl is more preferred. In some embodiments, C _1-4 haloalkoxy is particularly preferred, and C _1-2 haloalkoxy is more preferred. Exemplary haloalkyl groups include, but the are not limited _{_{to: -CF 3, -CH 2 F,}} -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary halogenated alkoxy groups include, but are not limited to: -OCH ₂ F, -OCHF ₂ , -OCF ₃ , and the like.

"C _3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C _3-7 cycloalkyl is preferred, C _3-6 cycloalkyl is particularly preferred, and C _5-6 cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in this case, the number of carbons continues to indicate The number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl ( C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptene Group (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1] Heptyl (C ₇ ), bicyclo[2.2.2]octyl (C ₈ ), cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthyl (C ₁₀ ), spiro[4.5]decyl (C ₁₀ ), and so on. Regardless of whether the cycloalkyl group is modified with "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The basis is defined as follows.

"3 to 10 membered heterocyclic group" or a group of 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen and oxygen , Sulfur, boron, phosphorus and silicon. In a heterocyclic group containing one or more nitrogen atoms, as long as the valence allows, the point of attachment may be a carbon or nitrogen atom. In some embodiments, a 3 to 7 membered heterocyclic group is preferred, which is a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3 to 6 The membered heterocyclic group is particularly preferred, which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5 to 6 membered heterocyclic group, which has ring carbon atoms and A 5- to 6-membered non-aromatic ring system with 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the aforementioned heterocyclyl ring is fused with one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in this case, the ring The number of members continues to indicate the number of ring members in the heterocyclyl ring system. Regardless of whether the heterocyclic group is modified with "substituted", each of the heterocyclic groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, as appropriate substitutions The basis is defined as follows.

Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxasulfuranyl. Oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiacyclohexyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thieppanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azacyclooctyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups fused to a C ₆ aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: indolinyl, isoindolinyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with C ₆ aryl rings (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.

"C _6-14 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6-14 ring carbon atoms and zero heteroatoms) The shared 6, 10, or 14 π electrons) groups are arranged in a ring. In some embodiments, an aryl group having six ring carbon atoms ( "C ₆ aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C ₁₀ aryl"; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (" _C14 aryl"; for example, anthryl). In some embodiments, C _6-10 aryl groups are particularly preferred, and C ₆ aryl groups are more preferred. The aryl group also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring. In this case, the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is modified with "substituted" in front of it, each of the aryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are as follows definition.

"5 to 10 membered heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (for example, having a shared ring arrangement 6 or 10 π electrons), where each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, as long as the valence allows, the point of attachment may be a carbon or nitrogen atom. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl groups also include ring systems in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case, the carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5- to 6-membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Regardless of whether the heteroaryl group is modified with "substituted" in front of it, each of the heteroaryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitably substituted The basis is defined as follows.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , Benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazole, Indenazinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pterridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON (R ^bb _{^{) 2, -N (R bb)}} 2, -N (R bb) 3 + X -, -N (OR cc) R bb, -SH, -SR aa, -SSR cc, -C (= O) R aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) _2. -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa ,- Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(= S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P( =O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ ,- NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and Heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^dd groups replace;

Or the two geminal hydrogens on the carbon atom are grouped by =0, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , = NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc replaced;

Each of ^Raa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl, or two ^Raa groups are combined to form a heterocyclic group or Heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^dd groups Group replacement

Each of R ^bb is independently selected from: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O ) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkene Group, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ^bb groups combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkyne Group, carbocyclic group, heterocyclic group, aryl group and heteroaryl group are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each of R ^cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^cc groups are combined to form a heterocyclic ring Group or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^dd group substitution;

Each of R ^dd is independently selected from: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N ^{_{(R ff) 2 ,, - N}} (R ff) 3 + X -, -N (OR ee) R ff, -SH, -SR ee, -SSR ee, -C (= O) R ee, -CO 2 H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ ,- NR ^ff C(=O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff ) R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee ,- SC(=S)SR ^ee , -P(=O) ₂ R ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group Group, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two geminal R ^dd substituents can be combined to form =O or =S;

Each of R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon Cyclic, heterocyclic, aryl and heteroaryl groups are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

Each of R ^ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ^ff groups are combined to form a heterocyclic group Or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^gg Group substitution

Each of R ^gg is independently: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON (C _1-6 alkyl) _2, -N (C _1-6 alkyl) _2, -N (C _1-6 _{^{^{alkyl) 3 + X -, -NH (}}} C 1-6 alkyl) _₂ ⁺ X ^-, -NH ₂ (C _1-6 ^{^{_{^{alkyl) + X -, -NH 3 +}}}} X -, -N (OC 1-6 alkyl) (C _1-6 alkyl), - N (OH) ( C 1-6 alkyl ), -NH(OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C(=O) (C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C (=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ ,- NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _{1- 6} alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl) , -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C (=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl , -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP(= O)(C _1-6 alkyl) ₂ , -OP( =0)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclic ring Group, C ₆ -C ₁₀ aryl group, C ₃ -C ₇ heterocyclic group, C ₅ -C ₁₀ heteroaryl group; or two geminal R ^gg substituents can be combined to form =O or =S; where X ^- is Counter ion.

Exemplary substituents on the nitrogen atom include but are not limited to: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) _2. -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O )(NR ^cc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl, or two R ^cc groups connected to a nitrogen atom combine to form a heterocyclic ring Group or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^{The dd} group is substituted, and wherein R ^aa , R ^bb , R ^cc and R ^{dd are} as described above.

"Deuteration" or "D" means that one or more hydrogens in a compound or group are replaced by deuterium; deuteration can be mono-, di-, poly, or full-substitution. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

"Non-deuterated compound" refers to a compound containing deuterium atoms not higher than the natural deuterium isotope content (0.015%).

The deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably Greater than 99%.

The term "pharmaceutically acceptable salt" means, within the scope of reliable medical judgment, suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergy, etc., and with reasonable benefits/risks Those salt in proportion. Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts described in detail by Berge et al. in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. It also includes salts formed using conventional methods in the art, for example, ion exchange methods. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , Malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. If appropriate, other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, Nitrate, lower alkylsulfonate and arylsulfonate.

"Active metabolite" refers to the pharmacologically active product metabolized in the body by the compound of formula (I) or its salt. The prodrugs and active metabolites of compounds can be determined using conventional techniques known or available in the industry.

"Subjects" to be administered include, but are not limited to: humans (ie, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults)) and/or non-human animals, for example, mammals, for example, primates (for example, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , Goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"Disease", "disorder" and "condition" are used interchangeably herein.

Unless otherwise specified, the term "treatment" as used herein includes the effect that occurs when a subject suffers from a specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder Or the development of a condition ("therapeutic treatment"), and also includes effects that occur before the subject begins to suffer from a specific disease, disorder, or condition ("preventive treatment").

"Combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compound of the present invention can be administered simultaneously or sequentially in separate unit dosage forms with another therapeutic agent, or simultaneously administered in a single unit dosage form with another therapeutic agent.

detailed description

Compound

Herein, "the compound of the present invention" refers to the following compound of formula (I) (including a subset of each formula), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In one embodiment, the present invention relates to compounds of formula (I):

among them,

· Ring A and Ring B form an aromatic fused ring;

· A ₃ and A ₄ are each independently selected from C atom or N atom;

A ₁ , A ₂ , A ₃ , A ₄ , A ₅ , A ₆ , A ₇ and A ₈

In a specific embodiment, A _{1 is} selected from NR ₁ ; in another specific embodiment, A _{1 is} selected from CR ₁ . In another specific embodiment, A _{1 is} selected from CH.

In a specific embodiment,

Selected from

In another specific embodiment,

Selected from

In another specific embodiment,

Selected from

In another specific embodiment,

Selected from

In another specific embodiment,

Selected from

In another specific embodiment,

Selected from

In another specific embodiment,

Selected from

In a specific embodiment,

Selected from

In another specific embodiment,

Selected from

In another specific embodiment,

Selected from

B ₁ , B ₂ , B ₃ and B ₄

In a specific embodiment, B ₁ , B ₂ , B ₃ and B ₄ are each independently selected from CR ^* or N; in another specific embodiment, B ₁ , B ₂ , B ₃ and B _{4 are} selected from CR ^* ; In another specific embodiment, B ₁ , B ₂ and B _{3 are} selected from CR ^* , and B _{4 is} selected from N; in another specific embodiment, B ₂ and B _{3 are} selected from CR ^* , and B ₁ and B _{4 are} selected from N.

In a specific embodiment,

Selected from

R ^*

In one specific embodiment, R ^* is independently selected from H, D, _{halogen, -CN, -R c, -C (} O) R c, -C (O) OR c, -C (O) NR c R _d , -NR _c R _d , -NR _c C(O)R _c , -OR _c , -OC(O)R _c , -OC(O)OR _c or -OC(O)NR _c R _d ; in In another specific embodiment, R ^{* is} each independently selected from H, D, halogen, CN or C _1-6 alkyl; in another specific embodiment, R ^{* is} each independently selected from H, F, Cl, Br, CN, methyl or -CD ₃ ; in another specific embodiment, each R ^{* is} independently selected from H or F; in another specific embodiment, each group defined by R ^* is optionally Substituted by one or more D until fully deuterated.

R, R ', L ₁ and R _a

In one particular embodiment, each R and R 'are each independently selected from H, halo, -CN, C _1-6 alkyl, or -L ₁ -R _a; In another embodiment, each R Each is independently selected from H, halogen, CN, or C _1-6 alkyl; in another specific embodiment, each R′ is independently selected from H, halogen, CN, C _1-6 alkyl, or -L ₁ -R _a ; In another specific embodiment, each R'is independently selected from H or -L ₁ -R _a .

In a specific embodiment of R and R', L _{1 is} selected from bonds; in another specific embodiment of R and R', L _{1 is} selected from NH.

The R and R 'in a particular embodiment, R _a is selected from phenyl or 5 to 6 membered heteroaryl containing 1-3 N, O or S heteroatom group, wherein said group is optionally substituted with a substituted or more R _b; in another particular embodiment, R _a is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl , Oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl, wherein said group is optionally substituted with one or more R _b ; in another specific embodiment, R _{a is} selected from Phenyl, pyrazolyl, imidazolyl, oxazolyl or isoxazolyl, wherein said group is optionally substituted with one or more R _b ; in another specific embodiment, R _{a is} selected from pyrazole An azole group, wherein the group is optionally substituted with one or more R _b .

In one particular embodiment, R _a is selected from

In another particular embodiment, R _a is selected from

In another particular embodiment, R _a is selected from

R _b

In a specific embodiment, each R _{b is} independently selected from H or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally halogen, -OH, -NH ₂ , -N( C _1-6 alkyl) ₂ , C _1-6 alkoxy, C _3-7 cycloalkyl or 3 to 7 membered heterocyclic group; in another specific embodiment, each R _{b is} independently selected From H or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally selected from halogen, -OH, -NH ₂ , -N(C _1-6 alkyl) ₂ or C _1-6 Alkoxy is substituted by one or more groups; in another specific embodiment, each R _{b is} independently selected from H, methyl, isopropyl, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ or -CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ ; in In another specific embodiment, each group defined by R _b is optionally substituted with one or more D until fully deuterated.

Ring C

In a specific embodiment, ring C is selected from phenyl or 5- to 6-membered heteroaryl containing 1-3 N, O or S heteroatoms, wherein said phenyl and 5- to 6-membered heteroaryl are either Is optionally substituted with one or more R _b' ; in another specific embodiment, ring C is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazole Group, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl, wherein said group is optionally substituted with one or more R _b' ; in another specific embodiment , Ring C is selected from phenyl, pyrazolyl, imidazolyl, oxazolyl or oxazolyl, wherein said group is optionally substituted by one or more R _b' ; in another specific embodiment, Ring C is selected from phenyl, pyridyl, oxazolyl or oxazolyl, wherein said group is optionally substituted with one or more R _b' ;

In another specific embodiment, ring C is selected from

In another specific embodiment, ring C is selected from

In another specific embodiment, ring C is selected from

Wherein, n is selected from 0, 1, 2 or 3.

R _b'

In one particular embodiment, each R _{b 'are} each independently selected from H, halo, C _1-6 alkyl, C _3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C _6-10 aryl, Or 5 to 10 membered heteroaryl, wherein the C _1-6 alkyl, C _3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C _6-10 aryl or 5 to 10 membered heteroaryl Optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C(O)C _1-6 alkyl,- C(O)OC _1-6 alkyl, -C(O)N(C _1-6 alkyl) ₂ , -OC(O)C _1-6 alkyl, -N(C _1-6 alkyl)C (O) C _1-6 alkyl or -N (C _1-6 alkyl) C (O) OC _1-6 alkyl substituted by one or more groups; in another specific embodiment, each R _b'is each independently selected from H or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted by one or more groups selected from halogen or C _1-6 haloalkyl ; in another embodiment, each R _{b 'are} each independently selected from _{_{F, -CH (CH 3) 2}} , -C (CH 3) 2 CH 2 OH, -CF 3, -C (CH 3) ₃ , -CF ₂ (CH ₃ ), -C(CH ₃ )(CH ₂ F) ₂ , -C(CH ₃ ) ₂ CF ₃ , -C(CF ₃ ) ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ F, -CF(CH ₃ ) ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

In another specific embodiment, each R _{b 'are} each independently selected from _{F, -CF 3, -C (CH} 3) 3, -C (CH 3) 2 CF 3 or -C (CF ₃₎ ₂ CH _3; in another specific embodiment, each group R _{b 'are} defined optionally substituted by one or more D, until completely deuterated.

L ₂ and L ₃

In a specific embodiment, L ₂ and L ₃ are each independently selected from bond, NH, CH ₂ , CHD or CD ₂ ; in another specific embodiment, L _{2 is} selected from bond; in another specific embodiment , L _{2 is} selected from NH; in another specific embodiment, L _{2 is} selected from CH ₂ ; in another specific embodiment, L _{2 is} selected from CHD; in another specific embodiment, L _{2 is} selected from CD ₂ ; In another specific embodiment, L _{3 is} selected from bonds; in another specific embodiment, L _{3 is} selected from NH; in another specific embodiment, L _{3 is} selected from CH ₂ ; in another specific embodiment Here, L _{3 is} selected from CHD; in another specific embodiment, L _{3 is} selected from CD ₂ .

In another embodiment, the invention relates to a compound of the formula:

among them,

W ₁ and V ₁ are each independently selected from CR _b or N;

W ₂ and V ₂ are each independently selected from CR _{b 'or} N;

Other parameters are defined as described above.

In another embodiment, the invention relates to a compound of the formula:

A ₃ and A ₄ are each independently selected from C atom or N atom, and there is one C atom and one N atom;

A ₅ and A ₆ are each independently selected from N atoms or C atoms, which are optionally substituted by R;

A ₇ and A ₈ are each independently selected from N atom or C atom, which is optionally substituted by R′;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R'is independently selected from H, D, halogen, -CN or -L ₁ -R _a ;

One of A ₇ and A ₈ is replaced by -L ₁ -R _a ;

Wherein, L ₁ is selected from a bond, O, or NH; R _a is

Where * indicates the connection position with L ₁ ;

B ₁ and B ₂ are each independently selected from CR ^* or N;

Wherein each R ^{* is} independently selected from H, D, halogen or -CN;

In another embodiment, the invention relates to a compound of the formula:

among them,

Wherein each R is independently selected from H, D, halogen or -CN;

Each R'is independently selected from H, D, halogen, -CN or -L ₁ -R _a ;

And at least one of A ₅ , A ₆ and A ₇ is N, and one of A ₇ and A ₈ is substituted by -L ₁ -R _a ;

Wherein, L ₁ is selected from a bond, O, or NH; R _a is

Where * indicates the connection position with L ₁ ;

B ₁ and B ₂ are each independently selected from CR ^* or N;

Wherein each R ^{* is} independently selected from H, D, halogen or -CN;

In another embodiment, the invention relates to a compound of the formula:

among them,

A _{7 is} selected from N atom or C atom, which is optionally substituted by R';

And at least one of A ₅ , A ₆ and A ₇ is N;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R'is independently selected from H, D, halogen or -CN;

In another embodiment, the invention relates to a compound of the formula:

among them,

A ₅ and A ₆ are each independently selected from N atoms or C atoms, which are optionally substituted by R, and at least one of them is a N atom;

B ₁ and B ₂ are each independently selected from CR ^* or N;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R ^{* is} independently selected from H, D, halogen or -CN;

Preferably, B ₁ and B ₂ are both CR ^* ;

In another embodiment, the invention relates to a compound of the formula:

among them,

A _{8 is} selected from N atom or C atom, which is optionally substituted by R′;

B ₁ and B ₂ are each independently selected from CR ^* or N;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R ^{* is} independently selected from H, D, halogen or -CN;

Preferably, at least one of A ₅ , A ₆ and A ₈ is a N atom; more preferably A ₅ is a N atom;

In a more specific embodiment, the invention relates to the following compounds:

The compounds of the present invention may include one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, Including racemate mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be Prepared by asymmetric synthesis.

"Tautomers" means that a functional group in some compounds changes its structure into another functional group isomer, and can quickly convert between each other, and the two isomers are in dynamic equilibrium. This kind of isomer is called tautomer.

Those skilled in the art will understand that an organic compound can form a complex with a solvent, which reacts in the solvent or precipitates or crystallizes out of the solvent. These complexes are called "solvates". When the solvent is water, the complex is called "hydrate". The present invention covers all solvates of the compounds of the present invention.

The term "solvate" refers to a compound or a salt form thereof combined with a solvent, which is usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, a hydrate of a compound can be represented by, for example, the general formula R·x H ₂ O, where R is the compound, and x is a number greater than zero. A given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5 H ₂ O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R·2 H ₂ O) and hexahydrate (R·6 H ₂ O)).

The compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic). In addition, the compounds of the present invention may exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compound of the present invention within its scope. The term "polymorph" refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compound can be prepared by crystallization under different conditions.

The present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by atoms having atomic mass or mass number different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. The compounds of the present invention containing the above isotopes and/or other isotopes of other atoms, their prodrugs, and the compounds or pharmaceutically acceptable salts of the prodrugs all fall within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those incorporating radioisotopes (e.g. ³ H and ¹⁴ C), can be used for drug and/or substrate tissue distribution determination. Tritium, ³ H and carbon-14, ¹⁴ C isotopes are particularly preferred because they are easy to prepare and detect. Further, substituted with heavier isotopes such as deuterium, i.e. ² H, may provide greater metabolic stability, since the therapeutic benefit, such as increased in vivo half-life or reduced dosage requirements, which in some cases may be preferred. Isotopically-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way. When performing the processes disclosed in the following procedures and/or examples and preparation examples, easily available isotope-labeled reagents are used instead of non-isotopes. Labeled reagents.

In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted into its active form with medical effects by, for example, hydrolysis in the blood in the body. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ASSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limits overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduced This article serves as a reference.

A prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in the body. Prodrugs are usually prepared by modifying functional groups, and the modification is performed in such a way that the modification can be performed by conventional operations or cleavage in vivo to produce the parent compound. Prodrugs include, for example, the compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group, which can be cleaved to form a hydroxyl, amino, or sulfhydryl group when administered to a patient. Therefore, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of the compound of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl and ethyl esters can be used. The ester itself can be active and/or can be hydrolyzed under human body conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or salt thereof.

Pharmaceutical compositions, preparations and kits

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains an effective amount of active ingredient. In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition includes a prophylactically effective amount of the active ingredient.

The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-inlay Segment polymers, polyethylene glycol and lanolin.

The invention also includes kits (e.g., pharmaceutical packaging). The kit provided may include the compound of the present invention, other therapeutic agents, and the first and second containers (for example, vials, ampoules, bottles, syringes, and/or dispersible packages or other Suitable container). In some embodiments, the provided kits may also optionally include a third container, which contains pharmaceutical excipients for diluting or suspending the compound of the present invention and/or other therapeutic agents. In some embodiments, the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.

The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Drugs, administration via implants or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , Intracerebrospinal drug delivery, intralesional drug delivery, and intracranial injection or infusion technology.

Generally, an effective amount of a compound provided herein is administered. According to relevant conditions, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient’s symptoms, etc., the doctor can determine the amount of the compound actually administered .

When used to prevent the conditions of the present invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on the doctor's advice and under the supervision of the doctor, and the dosage levels are as described above. Subjects at risk of developing a particular disorder generally include subjects with a family history of the disorder, or those subjects who are particularly sensitive to the development of the disorder as determined by genetic testing or screening.

The pharmaceutical compositions provided herein can also be administered chronically ("long-term administration"). Long-term administration refers to the administration of the compound or its pharmaceutical composition over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.

Various administration methods can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, for example, in order to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient. For example, an intramuscular or subcutaneous bolus dose allows the active ingredient to be released slowly, while a bolus injection delivered directly to the vein (for example, by IV infusion) can be more effective. The rapid delivery allows the concentration of the active ingredient in the blood to rise rapidly to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, to provide a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by continuous infusion.

Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate precise dosing, the composition is provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for human patients and other mammals, each unit containing a predetermined number of active substances suitable for producing the desired therapeutic effect and suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In this composition, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remaining part is useful for forming the desired administration form. Kinds of carriers or excipients and processing aids.

For oral doses, the representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, each dose provides about 0.01 to about 20 mg/kg of the compound of the present invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.

In order to provide a blood level similar to or lower than the injected dose, the transdermal dose is usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.

From about 1 to about 120 hours, especially 24 to 96 hours, the injection dose level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. In order to obtain a sufficient steady state level, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given. For human patients of 40 to 80 kg, the maximum total dose cannot exceed approximately 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid form may include, for example, any of the following components, or compounds with similar properties: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, mint, water Methyl salicylate or orange flavoring agent.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As mentioned before, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

The transdermal composition is typically formulated as a topical ointment or cream containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art, and usually include other components for enhancing the active ingredient or stable skin penetration of the formulation. All such known transdermal preparations and components are included within the scope provided by the present invention.

The compounds of the invention may also be administered via transdermal devices. Therefore, transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.

The above components of the composition for oral administration, injection or topical administration are only representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds of the invention can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation contains water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins composed of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or multiple substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

Indications

Provided herein is the treatment, prevention or amelioration by one or more of RET, Trk, FLT3, c-Kit, PDGFR and VEGFR kinase (including wild-type and/or mutant RET, Trk, FLT3, c-Kit, PDGFR and VEGFR One or more of kinases) modulate or otherwise affect diseases or disorders, or methods for one or more symptoms or causes thereof.

The present invention provides a method for treating a protein kinase-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or Invention of pharmaceutical compositions.

As used herein, the term "wild type" refers to the most common gene or allele found in an organism. In some specific embodiments, "wild-type" refers to a gene or allele without mutations.

As used herein, the term "cancer" refers to the abnormal growth of cells that proliferate in an uncontrolled manner and in some cases metastasize. Types of cancer include but are not limited to solid tumors, such as bladder, intestine, brain, breast, endometrial, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (Melanoma) or blood tumors (such as leukemia).

RET

In a specific embodiment, the compound of the present invention is an inhibitor of RET kinase, and can be used to treat, prevent or ameliorate diseases or diseases that are regulated or otherwise affected by one or more of RET wild-type and RET kinase domain mutants. Obstacles, or effectively treat, prevent or ameliorate one or more of its symptoms or causes in other ways. Such diseases or disorders include, but are not limited to, proliferative disorders that can be treated, prevented or controlled by modulating the various activities of kinases (including dimerization, ligand binding, and phosphotransferase activity) or by modulating the expression of kinases (such as Cancers, including blood cancers and solid tumors), and gastrointestinal diseases (IBS).

As used herein, the term "mutation of the RET kinase domain" refers to one or more mutations in the RET kinase domain, or alternatively, refers to the RET (protein itself becomes the "RET kinase domain) that includes one or more of the mutations. mutant"). Mutations in the RET kinase domain can be insertions, deletions or point mutations. In a specific embodiment, the mutation of the RET kinase domain includes at least one point mutation in the kinase domain. In another specific embodiment, the mutation of the RET kinase domain includes at least one point mutation in the kinase domain. In another specific embodiment, the point mutation in the RET kinase domain is selected from S32L, D34S, L40P, P64L, R67H, R ₁ 14H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, A ₅ 10V, E511K, C515S, C531R, G533C, G533S, G550E, V591I, G593E, I602V, R600Q, K603Q, K603E, Y606C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611C611W, C611F, C611F C618S, C618Y, C618R, C618Y, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, D631N, D631Y, D631Y D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A ₆ 40G, A ₆ 41S, A ₆ 41T, V648I, S649L, A ₆ 64D, H665Q, K666E, K666M, K666N, S686N, G691S, R694Q, M700L, V706M, V706A, E713K, G736R, G748C, A ₇ 50P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, L790F, Y791F, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, E818K, S819I, G823E, Y826M, R833C, P841L, P841P, E844L843D, R844W, R844Q, R844L M848T, I852M, A866W, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, R897Q, D898V, E901K, S904F, S904C, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918T M918L, A919 V, E921K, S922P, S922Y, T930M, F961L, R972G, R982C, M1009V, D1017N, V1041G, or M1064T. In another specific embodiment, the point mutation in the RET kinase domain is selected from: V804L, V804M, V804E, M918T, E805K, Y806C, Y806E, C634Y or C634W. In another specific embodiment, the RET kinase domain mutation further includes a RET gene fusion. In another specific embodiment, the RET gene fusion is selected from: BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA ₄ -RET, TRIM33-RET, ERC1-RET, ELKS-RET, RET- ELKS, FGFR ₁ OP-RET, RET-MBD1, RET-RAB61P2, RET-PCM1, RET-PPKAR ₁ A, RET-TRIM24, RET-RFG9, RFP-RET, RET-GOLGA ₅ , HOOK3-RET, KTN1-RET , TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR ₁ /RET, CEP55-RET, CUX1-RET, KIAA ₁ 468-RET, PPKAR ₁ A-RET, RFG8/RET, RET/RFG8, H4-RET, ACBD5-RET, PTCex9-RET, MYH13-RET, PIBF1-RET, KIAA ₁ 217-RET or MPRIP-RET; in another specific embodiment, the RET gene fusion is selected from: KIF5B-RET Or CCDC6-RET; in another specific embodiment, the point mutation in the kinase domain of KIF5B-RET and CCDC6-RET is selected from: V804L, V804M, V804E, M918T, E805K, Y806C, Y806E, C634Y, or C634W.

TRK

In a specific embodiment, the compound of the present invention is an inhibitor of Trk kinase, and can be used to treat, prevent or ameliorate diseases or diseases that are regulated or otherwise affected by one or more of Trk wild-type and Trk kinase domain mutants. Obstacles, or effectively treat, prevent or ameliorate one or more of its symptoms or causes in other ways. Such diseases or disorders include, but are not limited to, proliferative disorders that can be treated, prevented or controlled by modulating the various activities of kinases (including dimerization, ligand binding, and phosphotransferase activity) or by modulating the expression of kinases (such as Cancer, including blood cancers and solid tumors), as well as pain, inflammation and certain infectious diseases. In a specific embodiment, the cancer can be selected from: non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer , Prostate cancer, colon cancer, acute myeloid leukemia, sarcoma, pediatric glioma, intrahepatic cholangiocarcinoma, pilocytic astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland cancer, secretory breast Carcinoma, fibrosarcoma, kidney tumor and breast cancer.

In a specific embodiment, the Trk kinase is selected from TrkA, TrkB or TrkC.

The term "Trk kinase domain mutation" as used herein refers to one or more mutations in the Trk kinase domain, or alternatively, refers to a Trk including one or more of the mutations (the protein itself becomes the "Trk kinase domain mutant"). Mutations in the Trk kinase domain can be insertions, deletions or point mutations. In a specific embodiment, the mutation of the Trk kinase domain includes at least one point mutation in the kinase domain. In another specific embodiment, the mutation of the Trk kinase domain includes at least one point mutation in the kinase domain. In another specific embodiment, the point mutation in the Trk kinase domain is selected from G595R.

FLT3

In a specific embodiment, the compound of the present invention is an inhibitor of FLT3 kinase, and can be used to treat, prevent or ameliorate the regulation by one or more of FLT3 wild-type, FLT3-ITD and FLT3 kinase domain mutants or other The disease or disorder affected by the method, or one or more of its symptoms or causes are effectively treated, prevented, or improved in other ways. Such diseases or disorders include, but are not limited to, blood cancers that can be treated, prevented, or controlled by modulating various kinase activities (including dimerization, ligand binding, and phosphotransferase activity) or modulating kinase expression, including acute Myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), where such methods include administering treatment and treatment to subjects in need of such treatment, prevention or control, such as humans A prophylactically effective amount of the compound provided herein.

As used herein, the term "FLT3 kinase domain mutation" refers to one or more mutations in the FLT3 kinase domain, or alternatively, refers to FLT3 (the protein itself becomes the "FLT3 kinase domain) that includes one or more of the mutations. mutant"). Mutations in the FLT3 kinase domain can be insertions, deletions or point mutations. In a specific embodiment, the mutation of the FLT3 kinase domain includes at least one point mutation in the kinase domain. In another specific embodiment, the mutation of the FLT3 kinase domain includes at least one point mutation in the kinase domain. In another specific embodiment, the point mutation in the FLT3 kinase domain is at position E608, N676, F691, C828, D835, D839, N841, Y842, or M855. In another specific embodiment, the point mutation in the FLT3 kinase domain is selected from E608K, N676D, N676I, N676S, F691I, F691L, C828S, D835Y, D835V, D835H, D835F, D835E, D839G, D839H, N841C, Y842C, Y842H, Y842N, Y842S and M855T. In another specific embodiment, "FLT3 kinase domain mutation" refers to a point mutation at positions F691, D835 or Y842, or refers to FLT3 that includes at least one point mutation at those positions. In another specific embodiment, "FLT3 kinase domain mutation" refers to one or more point mutations selected from F691L, D835Y, D835V, D835H, D835F, D835E, Y842C, Y842H, Y842N and Y842S or to include at least one point mutation. The point mutation of FLT3. In another specific embodiment, the FLT3 kinase domain mutations further include one or more additional FLT3-ITD mutations. In another specific embodiment, the FLT3 kinase domain mutations further include one or more additional FLT3-ITD mutations. However, when the FLT3 kinase domain mutation includes more than one point mutation, another point mutation or mutation may appear on the same FLT3 receptor, or another point mutation or mutation may appear on a separate allele or on a different In leukemia pure lines, in this case, the mutation is polyclonal.

The term "proximal membrane region" or "proximal membrane domain" of FLT3 refers to the region of FLT3 that connects the transmembrane helix to the tyrosine kinase domain.

In another specific embodiment, "wild-type FLT3" refers to the FLT3 gene or allele, including allelic variants and mutations other than FLT3 kinase domain mutations and FLT3-ITD mutations.

c-KIT

In a specific embodiment, the compounds of the invention are inhibitors of c-Kit kinase and can be used to treat conditions associated with abnormal c-KIT activity. Activating mutations in c-KIT exist in a variety of indications, including systemic mastocytosis, gastrointestinal stromal tumors, acute leukemia, melanoma, seminoma, intracranial germ cell tumors and Mediastinal B-cell lymphoma.

In another specific embodiment, the compounds of the present invention can be used to treat one or more c-Kit mutations in exon 17 (e.g., D816V, D816Y, D816F, D816K, D816A, D816G, D820A, D820E, D820G, N822K, N822H, Y823D, and A829P) are active, but are much less active for wild-type c-Kit.

In the treatment methods of the present invention, "effective amount" is intended to refer to an amount or dose sufficient to produce the desired therapeutic benefit in an individual in need of the treatment. The effective amount or dosage of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation or clinical trials) and conventional factors (e.g., the mode or route of drug delivery, the pharmacokinetics of the agent, the severity and course of infection, and the individual Health status and weight, and the judgment of the treating physician). Exemplary dosages are in the range of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. The total dose can be single or divided dose units (e.g., BID, TID, QID).

After the patient's disease has improved, the dosage can be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration or both can be reduced to an amount that maintains the desired therapeutic or preventive effect based on symptoms. Of course, if the symptoms have been reduced to an appropriate level, treatment can be stopped. However, when any symptoms recur, the patient may require intermittent treatment for a long time. Patients may also require long-term slow treatment.

Drug combination

The compounds of the invention described herein can be used in pharmaceutical compositions or methods in combination with one or more other active ingredients to treat the diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or agents that mitigate the adverse effects of the therapeutic agent on the intended disease target. The combination can be used to increase efficacy, improve symptoms of other diseases, reduce one or more negative effects, or reduce the required dosage of the compound of the present invention. The additional active ingredient may be formulated into a pharmaceutical composition separate from the compound of the present invention or may be included in a single pharmaceutical composition with the compound of the present invention. The additional active ingredient may be administered at the same time, before or after the administration of the compound of the invention.

Combination agents include those additional active ingredients that are known or observed to be effective in the treatment of the diseases and conditions described herein, including those that are effective against another disease-related target. For example, the compositions and preparations and treatment methods of the present invention may further include other drugs or medicines, such as other active agents that can be used to treat or alleviate the target disease or related symptoms or conditions. For cancer indications, other such agents include (but are not limited to) kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); Raf inhibitors (e.g., Vero Vemurafenib), VEGFR inhibitors (for example, sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs , Mitosis inhibitors, antibodies, hormone therapy or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory agents, such as NSAIDs. The pharmaceutical composition of the present invention may additionally include one or more of the active agents, and the treatment method may additionally include administering an effective amount of one or more of the active agents.

Example

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, parts and percentages are parts by weight and percentages by weight.

Generally, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.

The abbreviations used in this article have the following meanings:

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

cataCXium A: n-butyl bis (1-adamantyl) phosphine

B ₂ pin ₂ : Pinacol diborate

NBS: N-bromosuccinimide

DMAP: 4-Dimethylaminopyridine

HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate

TEA: Triethylamine

DIEA: N,N-Diisopropylethylamine

Na ₂ CO ₃ ：Sodium carbonate

CsF: Cesium fluoride

LiOH: lithium hydroxide

HAc: Acetic acid

pTSA: p-toluenesulfonic acid

IPA: isopropanol

MeOH: methanol

EtOH: ethanol

H ₂ O: water

DCM: Dichloromethane

DCE: 1,2-Dichloroethane

THF: Tetrahydrofuran

ACN: Acetonitrile

DME: Dimethyl ether

DMA: N,N-Dimethylacetamide

Example 1 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazole [1,2 -b)pyridazin-3-yl)phenyl)urea (Compound T-1) Preparation

The following synthetic route is adopted:

Step 1: Synthesis of compound 7-chloroimidazo[1,2-b]pyridazine

5-Chloropyridazin-3-amine (0.84g, 6.5mmol) and 40% chloroacetaldehyde aqueous solution (2.55g, 19.5mmol) were added to 15mL of isopropanol and heated to reflux for 3 hours. The solvent was evaporated by rotary evaporation, diluted with 30mL water, extracted with ethyl acetate (20mL*3), combined the organic phases, washed with 20mL saturated brine, dried over anhydrous sodium sulfate, concentrated, separated by silica gel column to obtain 0.79g of light yellow solid , The yield is 80%. ESI-MS: 154[M ⁺ +1].

Step 2: Synthesis of compound 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine

The 7-chloroimidazo[1,2-b]pyridazine (0.79g, 5.2mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1H-pyrazole (1.35g, 6.5mmol), Pd(dppf)Cl ₂ (190mg, 0.26mmol) and Na ₂ CO ₃ (1.65g, 15.6mmol) were added To 20mL DME and 5mL water, replace with nitrogen three times, and increase the temperature to 90°C to react overnight. The reaction solution was cooled to room temperature, and 40 mL of water was added to quench the reaction. The reaction was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain a pale yellow solid 0.67g, the yield is 65%. ESI-MS: 200[M ⁺ +1].

Step 3: Synthesis of compound 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine

Dissolve 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (0.67g, 3.4mmol) in 10mL acetonitrile, slowly add NBS (0.66g, 3.7mmol) ), stirring at room temperature for 2 hours. The solvent was evaporated by rotary evaporation, diluted with 10mL water, extracted with ethyl acetate (10mL*3), the organic phase was washed with 10mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 0.8g of light yellow solid. The yield was 85%. ESI-MS: 280[M ⁺ +2].

Step 4: Compound 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolan-2-yl)phenyl)urea

4-Aminophenylboronic acid pinacol ester (0.88g, 4mmol) was dissolved in 15mL of tetrahydrofuran, bis(trichloromethyl)carbonate (0.41g, 1.4mmol) was slowly added, and the temperature was raised and refluxed for 1 hour. Rotate to evaporate the solvent, add 20mL of tetrahydrofuran to dissolve, add DMAP (49mg, 0.4mmol), triethylamine (0.81g, 8mmol) and 2-fluoro-5-trifluoromethylaniline (0.71g, 4mmol), and reflux React overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and it was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 0.93 g of light yellow solid. The rate is 55%. ESI-MS: 425[M ⁺ +1].

Step 5: Compound 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1 ,2-b)Pyridazin-3-yl)phenyl)urea (Compound T-1)

Add 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (86mg, 0.31mmol), 1-(2-fluoro-5-( Trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (156mg, 0.37mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (131mg, 1.24mmol) were added to 12mL DME and 4mL water, replaced with nitrogen three times, heated to 90°C and reacted overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain 100 mg of light yellow solid. The rate is 66%. ESI-MS: 496[M ⁺ +1]. ¹ H NMR(300MHz,DMSO-d ₆ )δ9.37(s,1H),8.97(s,2H),8.64(d,J=7.3Hz,1H), 8.40(d,J=27.0Hz,2H) , 8.14 (dd, J = 21.5, 8.4 Hz, 4H), 7.62 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 10.2 Hz, 1H), 7.40 (s, 1H), 3.91 (s, 3H).

Example 2 2-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)phenyl)-N-(5 -(1,1,1-trifluoro-2-methylpropane -2-yl)isoxazol-3-yl)acetamide (compound T-2)

The following synthetic route is adopted:

Step 1: Compound 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5- Synthesis of (1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide

The 4-(carboxymethyl)phenylboronic acid pinacol ester (0.94g, 3.6mmol), 5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazole-3 -Amine (0.7g, 3.6mmol) and triethylamine (0.73g, 7.2mmol) were dissolved in 20mL of dichloromethane, HATU (2.05g, 5.4mmol) was added under ice bath, and reacted at room temperature overnight. The reaction solution was diluted with 20 mL of dichloromethane, washed with water, the organic phase was washed with 10 mL of saturated brine, dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 1.1 g of light yellow solid, with a yield of 70%. ESI-MS: 439[M ⁺ +1].

Step 2: Compound 2-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)phenyl)-N-( Synthesis of 5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide

Add 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (83mg, 0.3mmol), 2-(4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro-2-methyl Propan-2-yl)isoxazol-3-yl)acetamide (158mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (127mg, 1.2mmol) were added to 10mL DME Replace it with 2 mL of water, replace it with nitrogen three times, and increase the temperature to 90° C. to react overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain 100 mg of light yellow solid. The rate is 66%. ESI-MS: 510[M ⁺ +1]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.45 (s, 1H), 9.58 (s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.80-- 7.64(m, 3H), 7.52(d, J=7.8Hz, 2H), 6.93(s, 1H), 3.90(s, 3H), 3.78(s, 2H), 1.54(s, 6H).

Example 3 2-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl)pyridin-3-yl)-N- (5-(1,1,1-Trifluoro-2-methyl Preparation of propyl-2-yl)isoxazol-3-yl)acetamide (compound T-3)

The following synthetic route is adopted:

Step 1: Synthesis of compound 7-chloroimidazo[1,2-c]pyrimidine

4-Amino-6-chloropyrimidine (0.84 g, 6.5 mmol) and 40% chloroacetaldehyde aqueous solution (2.55 g, 19.5 mmol) were added to 15 mL of isopropanol and heated to reflux for 3 hours. The solvent was evaporated by rotary evaporation, diluted with 30mL water, extracted with ethyl acetate (20mL*3), combined the organic phases, washed with 20mL saturated brine, dried over anhydrous sodium sulfate, concentrated, separated by silica gel column to obtain 0.79g of light yellow solid , The yield is 80%. ESI-MS: 154[M ⁺ +1].

Step 2: Synthesis of compound 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine

The 7-chloroimidazo[1,2-c]pyrimidine (0.79g, 5.2mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxide Heteroborolan-2-yl)-1H-pyrazole (1.35g, 6.5mmol), Pd(dppf)Cl ₂ (190mg, 0.26mmol) and Na ₂ CO ₃ (1.65g, 15.6mmol) were added to 20mL DME and 5mL water were replaced with nitrogen three times, and the temperature was raised to 90°C to react overnight. The reaction solution was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 0.67 g of light yellow solid. The yield was 65%. ESI-MS: 200[M ⁺ +1].

Step 3: Synthesis of compound 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine

Dissolve 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.67g, 3.4mmol) in 10mL acetonitrile, slowly add NBS (0.66g, 3.7mmol) , Stir at room temperature for 2 hours. The solvent was evaporated by rotary evaporation, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 0.8 g of light yellow solid. The rate is 85%. ESI-MS: 280[M ⁺ +2].

Step 4: Compound 2-(6-Bromopyridin-3-yl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl) Synthesis of acetamide

The 2-(6-bromopyridin-3-yl)acetic acid (1.02g, 4.7mmol), 5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazole-3- Amine (0.92g, 4.7mmol) and DIEA (1.21g, 9.4mmol) were dissolved in 20mL of dichloromethane, HATU (2.66g, 7mmol) was added under ice bath and reacted at room temperature overnight. The reaction solution was diluted with 20 mL of dichloromethane, washed with water, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 1.3 g of light yellow solid with a yield of 70%. ESI-MS: 393[M ⁺ +1].

Step 5: Compound 2-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl)pyridin-3-yl)-N -(5-(1,1,1-Trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-3)

The 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (109mg, 0.39mmol), 2-(6-bromopyridin-3-yl) )-N-(5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (153mg, 0.39mmol), B ₂ pin ₂ (147mg , 0.58mmol), Pd(OAc) ₂ (9mg, 0.04mmol), n-butylbis(1-adamantyl)phosphine (29mg, 0.08mmol) and cesium fluoride (118mg, 0.78mmol) were added to 15mL of methanol and Replace with nitrogen three times in 4 mL of water, and increase the temperature to 60° C. and react for 4 hours. The reaction solution was cooled to room temperature, 30 mL of water was added, and it was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 60 mg of light yellow solid. The rate is 30%. ESI-MS: 511[M ⁺ +1]. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.45(s,1H),9.38(s,1H),8.52(s,1H),8.30(s,1H),7.90(s,1H),7.75( s, 1H), 7.56 (s, 1H), 7.49 (d, J = 7.8 Hz, 2H), 6.96 (s, 1H), 3.90 (s, 3H), 3.78 (s, 2H), 1.54 (s, 6H) ).

Example 4 2-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl)phenyl)-N-(5- (1,1,1-Trifluoro-2-methylpropane -2-yl)isoxazol-3-yl)acetamide (Compound T-4)

The following synthetic route is adopted:

Add 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (83mg, 0.3mmol), 2-(4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro-2-methylpropane -2-yl)isoxazol-3-yl)acetamide (158mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (127mg, 1.2mmol) were added to 10mL DME and Replace with nitrogen for three times in 2 mL of water, and increase the temperature to 90°C for overnight reaction. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain 100 mg of light yellow solid. The rate is 65%. ESI-MS: 510[M ⁺ +1]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.45 (s, 1H), 9.38 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.81-- 7.68 (m, 3H), 7.49 (d, J = 7.8 Hz, 2H), 6.96 (s, 1H), 3.90 (s, 3H), 3.78 (s, 2H), 1.54 (s, 6H).

Example 5 2-(4-(8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)phenyl)-N -(5-(1,1,1-trifluoro-2-methyl Preparation of propyl-2-yl)isoxazol-3-yl)acetamide (compound T-5)

The following synthetic route is adopted:

Step 1: Synthesis of compound 8-chloroimidazo[1,2-a]pyrazine

3-Chloropyrazine-2-amine (1.29 g, 10 mmol) and chloroacetaldehyde (40% aqueous solution, 9.8 g, 50 mmol) were added to 30 mL of isopropanol and heated to reflux overnight. Rotate to evaporate the solvent, add 30mL of water to dissolve, adjust PH=7 with saturated sodium bicarbonate solution, extract with ethyl acetate (20mL*3), combine the organic phases, wash with 20mL saturated brine, dry with anhydrous sodium sulfate, and concentrate , Separated by silica gel column to obtain 1.07 g of light yellow solid with a yield of 70%. ESI-MS: 154[M ⁺ +1].

Step 2: Synthesis of compound 3-bromo-8-chloroimidazo[1,2-a]pyrazine

Dissolve 8-chloroimidazo[1,2-a]pyrazine (1.07g, 7mmol) in 15mL of glacial acetic acid, slowly add liquid bromine (1.12g, 7mmol) under ice bath, remove the ice bath after the addition, Stir at room temperature overnight. TLC detects that the reaction is complete. Add 30mL saturated sodium sulfite solution, extract with ethyl acetate (30mL*3), combine the organic phases, wash with 20mL saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate by silica gel column to get light 1.33 g of yellow solid, yield 82%. ESI-MS: 234[M ⁺ +2].

Step 3: Synthesis of compound 3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazine-8-amine

Combine 3-bromo-8-chloroimidazo[1,2-a]pyrazine (1.33g, 5.7mmol), 1-methyl-1H-pyrazole-4-amine (0.66g, 6.8mmol) and triethyl Amine (1.15 g, 11.4 mmol) was added to 15 mL of n-butanol, and the temperature was raised to 120° C. to react overnight. The solvent was evaporated by rotary evaporation, diluted with 30mL water, extracted with ethyl acetate (20mL*3), combined the organic phases, washed with 20mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 1.25g of light yellow solid , The yield is 75%. ESI-MS: 295[M ⁺ +2].

Step 4: Compound 2-(4-(8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)phenyl)- Synthesis of N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (compound T-5)

The 3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazine-8-amine (88mg, 0.3mmol), 2-(4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro- 2-Methylpropan-2-yl)isoxazol-3-yl)acetamide (158mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (127mg, 1.2mmol) Added to 10mL DME and 2mL water, replaced with nitrogen three times, heated to 90°C and reacted overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 94 mg of light yellow solid. The rate is 60%. ESI-MS: 525[M ⁺ +1]. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.46(s,1H),9.91(s,1H),8.19(s,1H),8.11(d,J=8.3Hz,2H),8.02(s,1H) ), 7.94 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 6.96 (s, 1H), 3.83 (s, 3H), 3.79 (s, 2H), 1.53 (s, 1H).

Example 6 2-(4-(8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)phenyl)-N -(5-(1,1,1-trifluoro-2-methyl Preparation of propyl-2-yl)isoxazol-3-yl)acetamide (compound T-6)

The following synthetic route is adopted:

Step 1: Synthesis of compound 8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine

Benzyl alcohol (1.2 g, 11 mmol) was dissolved in 20 mL of tetrahydrofuran, sodium hydride (60%, dispersed in liquid paraffin, 0.44 g, 11 mmol) was added under ice bath, and stirred at room temperature for half an hour. Slowly add 8-bromo-6-chloroimidazo[1,2-b]pyridazine (2.32g, 10mmol) under ice bath, remove the ice bath, and react at room temperature overnight. TLC detects that the reaction is complete. Dilute with 30mL water. The reaction solution is extracted with ethyl acetate (20mL*3). The organic phases are combined, washed with 20mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain a pale yellow solid. 2.24g, yield 86.5%. ESI-MS: 260[M ⁺ +1].

Step 2: Synthesis of compound imidazo[1,2-b]pyridazine-8-ol

Dissolve 8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine (2.24g, 8.6mmol) in 20mL methanol, add 200mg 10% palladium on carbon, replace with hydrogen three times, Stir at room temperature overnight under atmospheric hydrogen atmosphere. After the reaction was completed, the palladium/carbon was filtered off, the filtrate was concentrated and dried to obtain 1.05 g of white solid with a yield of 90%. ESI-MS: 136[M ⁺ +1].

Step 3: Synthesis of compound imidazo[1,2-b]pyridazine-8-yl 4-methylbenzenesulfonate

Add imidazo[1,2-b]pyridazine-8-ol (1.05g, 7.8mmol) and triethylamine (1.58g, 15.6mmol) to 20mL of dichloromethane, add 4-methyl under ice bath Benzenesulfonyl chloride (1.8 g, 9.4 mmol) was reacted at room temperature for 2 hours, and the reaction was complete as determined by TLC. The reaction solution was washed with 20 mL of water and 10 mL of saturated brine, dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 2.06 g of white solid with a yield of 92%. ESI-MS: 290[M ⁺ +1].

Step 4: Synthesis of compound 3-bromoimidazo[1,2-b]pyridazin-8-yl 4-methylbenzenesulfonate

Dissolve imidazo[1,2-b]pyridazine-8-yl 4-methylbenzenesulfonate (2.06g, 7.1mmol) in 20mL of dichloromethane, add NBS (1.34g, 7.5mmol) under ice bath , React at room temperature for 2 hours, TLC detects the reaction is complete. The reaction solution was washed with 20 mL of water, dried with anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 2.1 g of a light yellow solid with a yield of 80%. ESI-MS: 370[M ⁺ +2].

Step 5: Synthesis of compound 3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-amine

The 3-bromoimidazo[1,2-b]pyridazine-8-yl 4-methylbenzenesulfonate (2.1g, 5.7mmol), 1-methyl-1H-pyrazole-4-amine (0.66 g, 6.8 mmol) and triethylamine (1.15 g, 11.4 mmol) were added to 15 mL of n-butanol, and the temperature was raised to 120° C. to react overnight. Rotate to evaporate the solvent, add 30mL of water to dilute, extract with ethyl acetate (20mL*3), combine the organic phases, wash with 20mL of saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate on a silica gel column to obtain a pale yellow solid 1.25g , The yield is 75%. ESI-MS: 295[M ⁺ +2].

Step 6: Compound 2-(4-(8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)phenyl)- Synthesis of N-(5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-6)

The 3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-amine (88mg, 0.3mmol), 2-(4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro- 2-Methylpropan-2-yl)isoxazol-3-yl)acetamide (158mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (127mg, 1.2mmol) Added to 10mL DME and 2mL water, replaced with nitrogen three times, heated to 90°C and reacted overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain 86 mg of light yellow solid. The rate is 55%. ESI-MS: 525[M ⁺ +1]. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.42(s,1H),9.32(s,1H), 8.19(d,J=5.6Hz,1H), 8.10(d,J=8.3Hz,2H), 8.01(s,1H),7.92(s,1H),7.58(s,1H),7.43(d,J=8.2Hz,2H),6.95(s,1H),6.37(d,J=5.6Hz,1H ), 3.85(s, 3H), 3.74(s, 2H), 1.53(s, 6H).

Example 7 2-(2-Fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)phenyl)- N-(5-(1,1,1-trifluoro-2-methyl Preparation of propyl-2-yl)isoxazol-3-yl)acetamide (compound T-7)

The following synthetic route is adopted:

Step 1: Compound 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N -(5-(1,1,1-Trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide

The 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (0.94g, 3.6mmol), 5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-amine (0.7g, 3.6mmol) and triethylamine (0.73g, 7.2mmol ) Was dissolved in 20 mL of dichloromethane, HATU (2.05 g, 5.4 mmol) was added under ice bath, and reacted at room temperature overnight. The reaction solution was diluted with 20 mL of dichloromethane, washed with water, the organic phase was washed with 10 mL of saturated brine, dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 1.1 g of light yellow solid, with a yield of 70%. ESI-MS: 457[M ⁺ +1].

Step 2: Compound 2-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)phenyl) -N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (compound T-7)

The 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (83mg, 0.3mmol), 2-(2-fluoro-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro- 2-Methylpropan-2-yl)isoxazol-3-yl)acetamide (164mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (127mg, 1.2mmol) Added to 10mL DME and 2mL water, replaced with nitrogen three times, heated to 90°C and reacted overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 95 mg of pale yellow solid. The rate is 60%. ESI-MS: 528[M ⁺ +1]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.46 (s, 1H), 9.04 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.20 ( s, 1H), 8.06 (d, J = 11.6 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 6.96 (s, 1H), 3.91 (s, 3H), 3.85 (s, 2H), 1.54 (s, 6H).

Example 8 2-(2-Fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl)phenyl)-N -(5-(1,1,1-trifluoro-2-methyl Preparation of propyl-2-yl)isoxazol-3-yl)acetamide (compound T-8)

The following synthetic route is adopted:

Add 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (83mg, 0.3mmol), 2-(2-fluoro-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro-2 -Methylpropan-2-yl)isoxazol-3-yl)acetamide (164mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (127mg, 1.2mmol) were added Into 10mL DME and 2mL water, replace with nitrogen three times, and increase the temperature to 90°C to react overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and it was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 90 mg of light yellow solid. The rate is 57%. ESI-MS: 528[M ⁺ +1]. ¹ H NMR(400MHz, DMSO-d ₆ )δ11.46(s,1H), 9.24(s,1H), 8.52(s,1H), 8.38(s,1H), 8.30(s,1H), 8.21( s, 1H), 8.05 (d, J = 11.6 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 6.96 (s, 1H), 3.90 (s, 3H), 3.84 (s, 2H), 1.54 (s, 6H).

Example 9 2-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)-N -(5-(1,1,1-trifluoro-2-methyl Preparation of propyl-2-yl)isoxazol-3-yl)acetamide (compound T-9)

The following synthetic route is adopted:

Add 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (109mg, 0.39mmol), 2-(6-bromopyridine-3- Yl)-N-(5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (153mg, 0.39mmol), B ₂ pin ₂ ( 147mg, 0.58mmol), Pd(OAc) ₂ (9mg, 0.04mmol), n-butylbis(1-adamantyl)phosphine (29mg, 0.08mmol) and cesium fluoride (118mg, 0.78mmol) were added to 15mL methanol It was replaced with 4 mL of water with nitrogen three times, and the temperature was raised to 60° C. to react for 4 hours. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain 55 mg of pale yellow solid. The rate is 27%. ESI-MS: 511[M ⁺ +1]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.45 (s, 1H), 9.42 (s, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.76 ( s, 1H), 7.53 (s, 1H), 7.44 (d, J = 7.8 Hz, 2H), 6.95 (s, 1H), 3.91 (s, 3H), 3.79 (s, 2H), 1.54 (s, 6H) ).

Example 10 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-N-(5 -(1,1,1-trifluoro-2-methylpropane -2-yl)isoxazol-3-yl)acetamide (Compound T-10)

The following synthetic route is adopted:

Step 1: Synthesis of compound 6-bromopyrazolo[1,5-a]pyrimidine

1H-pyrazol-3-amine (0.63 g, 7.6 mmol) and 2-bromomalonaldehyde (1.15 g, 7.6 mmol) were added to 15 mL of absolute ethanol and 5 mL of glacial acetic acid, and reacted at 80° C. for 2 hours. The solvent was evaporated by rotary evaporation, diluted with 40mL water, extracted with ethyl acetate (30mL*3), the organic phase was washed with saturated sodium bicarbonate solution (30mL) and saturated brine (30mL), dried with anhydrous sodium sulfate, concentrated, 1.05 g of light yellow solid was separated by silica gel column with a yield of 70%. ESI-MS: 200[M ⁺ +2].

Step 2: Synthesis of compound 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine

The 6-bromopyrazolo[1,5-a]pyrimidine (1.03g, 5.2mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1H-pyrazole (1.35g, 6.5mmol), Pd(dppf)Cl ₂ (190mg, 0.26mmol) and Na ₂ CO ₃ (1.65g, 15.6mmol) were added To 20mL DME and 5mL water, replace with nitrogen three times, and increase the temperature to 90°C to react overnight. The reaction solution was cooled to room temperature, and 40 mL of water was added to quench the reaction. The reaction was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain a pale yellow solid 0.67g, the yield is 65%. ESI-MS: 200[M ⁺ +1].

Step 3: Synthesis of compound 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine

Dissolve 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (0.67g, 3.4mmol) in 10mL acetonitrile, slowly add NBS (0.66g, 3.7mmol) ), stirring at room temperature for 2 hours. The solvent was evaporated by rotary evaporation, diluted with 10mL water, extracted with ethyl acetate (10mL*3), the organic phase was washed with 10mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 0.8g of light yellow solid. The yield was 85%. ESI-MS: 280[M ⁺ +2].

Step 4: Compound 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-N-( Synthesis of 5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (compound T-10)

Add 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (86mg, 0.31mmol), 2-(4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro-2-methyl Propan-2-yl)isoxazol-3-yl)acetamide (158mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (131mg, 1.24mmol) were added to 12mL DME It was replaced with 4 mL of water with nitrogen for three times, and the temperature was raised to 90° C. to react overnight. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain 100 mg of light yellow solid. The rate is 63%. ESI-MS: 510[M ⁺ +1]. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.45(s,1H),9.58(s,1H),9.12(s,1H),8.45(s,1H),7.90(s,1H),7.80-- 7.64(m, 3H), 7.50(d, J=7.8Hz, 2H), 6.94(s, 1H), 3.90(s, 3H), 3.78(s, 2H), 1.54(s, 6H).

Example 11 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)phenyl)-N-(5 -(1,1,1-trifluoro-2-methylpropane -2-yl)isoxazol-3-yl)acetamide (compound T-11)

The following synthetic route is adopted:

Step 1: Synthesis of compound 1-amino-3-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate

Dissolve 2,4,6-trimethylbenzenesulfonyl hydroxylamine (10.8g, 50mmol) in 100mL of dichloromethane, slowly add 3-bromopyridine (8.69g, 55mmol) dropwise under ice bath, and leave at room temperature. After reacting for 2 hours, a white solid gradually precipitated. Add 200 mL of methyl tert-butyl ether, continue stirring for 20 minutes, filter, wash the filter cake with 100 mL of methyl tert-butyl ether, and place the solid in a vacuum oven at 55° C. and dry for 4 hours to obtain 15 g of a white solid with a yield of 80%.

Step 2: Synthesis of compound 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester

Dissolve 1-amino-3-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate (15g, 40mmol) in 60mL of anhydrous DMF and triethylamine (8.08g, 80mmol). Ethyl propiolate (7.8 g, 80 mmol) was slowly added dropwise under the bath, the ice bath was removed after the dropwise addition, and the mixture was stirred at room temperature for 48 hours. The reaction solution was diluted with 200 mL of water and extracted with ethyl acetate (60 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 2.4 g of light yellow solid. Yield twenty two%. ESI-MS: 271[M ⁺ +2].

Step 3: Synthesis of compound 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester

Ethyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.4g, 5.2mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)-1H-pyrazole (1.35g, 6.5mmol), Pd(dppf)Cl ₂ (190mg, 0.26mmol) and Na ₂ CO ₃ (1.65 g, 15.6 mmol) was added to 20 mL DME and 5 mL water, replaced with nitrogen three times, and heated to 90° C. to react overnight. The reaction solution was cooled to room temperature, and 40 mL of water was added to quench the reaction. The reaction was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain a pale yellow solid 1.02g, the yield was 73%. ESI-MS: 271[M ⁺ +1].

Step 4: Synthesis of compound 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Dissolve 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (1.02g, 3.8mmol) in 20mL ethanol and 10mL water, Sodium hydroxide (0.38g, 9.5mmol) was added and reacted at 80°C for 2 hours. Add 30mL of water to the reaction solution to dilute, adjust the pH to 3-4 with 1N hydrochloric acid, extract with ethyl acetate (30mL*3), wash the organic phase with 20mL of saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate on a silica gel column 0.82 g of light yellow solid was obtained, and the yield was 90%. ESI-MS: 243[M ⁺ +1].

Step 5: Synthesis of compound 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

Combine 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.82g, 3.4mmol) and sodium bicarbonate (0.86g, 10.2mmol ) Was dissolved in 15mL DMF, NBS (0.66g, 3.7mmol) was added in three batches, and stirred at room temperature for 5 hours. The reaction solution was diluted with 50mL water and extracted with ethyl acetate (30mL*3). The organic phase was washed with 20mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 0.85g of light yellow solid. Yield 80%. ESI-MS: 279[M ⁺ +2].

Step 6: Compound 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)phenyl)-N-( Synthesis of 5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (compound T-11)

The 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (86mg, 0.31mmol), 2-(4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro-2-methyl Propan-2-yl)isoxazol-3-yl)acetamide (158mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (131mg, 1.24mmol) were added to 12mL DME It was replaced with 4 mL of water with nitrogen for three times, and the temperature was raised to 90° C. to react overnight. The reaction solution was cooled to room temperature, 30mL of water was added, and the mixture was extracted with ethyl acetate (20mL*3). The organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain a pale yellow solid 71mg. The rate is 45%. ESI-MS: 509[M ⁺ +1]. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.45(s,1H),9.16(s,1H),8.58(s,1H),8.32(s,1H),8.11(d,J=8.3Hz, 1H), 7.90 (s, 1H), 7.80-7.64 (m, 4H), 7.43 (d, J = 8.2 Hz, 1H), 6.94 (s, 1H), 3.91 (s, 3H), 3.79 (s, 2H) ), 1.54(s, 6H).

Example 12 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-yl)phenyl)-N-( 5-(1,1,1-trifluoro-2-methylpropane -2-yl)isoxazol-3-yl)acetamide (compound T-12)

The following synthetic route is adopted:

Step 1: Synthesis of compound 1-amino-3-bromopyrazine-1-ium 2,4,6-trimethylbenzenesulfonate

Dissolve 2,4,6-trimethylbenzenesulfonyl hydroxylamine (10.8g, 50mmol) in 100mL of dichloromethane, slowly add 3-bromopyrazine (8.69g, 55mmol) dropwise to room temperature under ice bath After reacting for 2 hours, a white solid gradually precipitated. Add 200 mL of methyl tert-butyl ether, continue stirring for 20 minutes, filter, wash the filter cake with 100 mL of methyl tert-butyl ether, and place the solid in a vacuum oven at 55° C. and dry for 4 hours to obtain 15 g of a white solid with a yield of 80%.

Step 2: Synthesis of compound 6-bromopyrazolo[1,5-a]pyrazine-3-carboxylic acid ethyl ester

Dissolve 1-amino-3-bromopyrazine-1-ium 2,4,6-trimethylbenzenesulfonate (15g, 40mmol) in 60mL of anhydrous DMF and triethylamine (8.08g, 80mmol), Ethyl propiolate (7.8 g, 80 mmol) was slowly added dropwise under an ice bath, the ice bath was removed after the addition, and the mixture was stirred at room temperature for 48 hours. The reaction solution was diluted with 200mL water and extracted with ethyl acetate (60mL*3). The organic phase was washed with 10mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain a light yellow solid 1.6g. Yield 15%. ESI-MS: 272[M ⁺ +2].

Step 3: Synthesis of compound 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid ethyl ester

Ethyl 6-bromopyrazolo[1,5-a]pyrazine-3-carboxylate (1.4g, 5.2mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazole (1.35g, 6.5mmol), Pd(dppf)Cl ₂ (190mg, 0.26mmol) and Na ₂ CO ₃ ( 1.65g, 15.6mmol) was added to 20mL DME and 5mL water, replaced with nitrogen three times, heated to 90°C and reacted overnight. The reaction solution was cooled to room temperature, and 40 mL of water was added to quench the reaction. The reaction was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain a pale yellow solid 0.98g, yield 70%. ESI-MS: 272[M ⁺ +1].

Step 4: Synthesis of compound 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid

Ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (0.98g, 3.6mmol) was dissolved in 20mL ethanol and 10mL water Add sodium hydroxide (0.38g, 9.5mmol), and react at 80°C for 2 hours. Add 30mL of water to the reaction solution to dilute, adjust the pH to 3-4 with 1N hydrochloric acid, extract with ethyl acetate (30mL*3), wash the organic phase with 20mL of saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate on a silica gel column 0.82 g of light yellow solid was obtained, and the yield was 94%. ESI-MS: 244[M ⁺ +1].

Step 5: Synthesis of compound 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

Combine 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (0.82g, 3.4mmol) and sodium bicarbonate (0.86g, 10.2 mmol) was dissolved in 15mL DMF, NBS (0.66g, 3.7mmol) was added in three batches, and stirred at room temperature for 5 hours. The reaction solution was diluted with 50mL water, extracted with ethyl acetate (30mL*3), the organic phase was washed with 20mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 0.68g of light yellow solid, yield 72%. ESI-MS: 280[M ⁺ +2].

Step 6: Compound 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-yl)phenyl)-N- Synthesis of (5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (compound T-12)

Add 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (86mg, 0.31mmol), 2-(4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1-trifluoro-2-methyl 2-yl)isoxazol-3-yl)acetamide (158mg, 0.36mmol), Pd(dppf)Cl ₂ (15mg, 0.02mmol) and Na ₂ CO ₃ (131mg, 1.24mmol) were added to 12mL DME and 4mL water were replaced with nitrogen three times, and the temperature was raised to 90°C for overnight reaction. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 80 mg of light yellow solid. The rate is 51%. ESI-MS: 510[M ⁺ +1]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.45 (s, 1H), 9.16 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.91 ( s, 1H), 7.85–7.62 (m, 4H), 6.86 (s, 1H), 3.91 (s, 3H), 3.78 (s, 2H), 1.54 (s, 6H).

Biological activity test

Biological Example 1: Kinase inhibition

(1) Kinase inhibition

Reagents and consumables:

Ret wt (Carna, catalog number 08-159-10ug), RET (V804M), Active (Signalchem, catalog number R02-12GG), HTRF KinEASE-TK kit (Cisbio, catalog number 62TK0PEC), CEP-32496 (MCE, Catalog number HY-15200), ATP (Sigma, catalog number A7699), DMSO (Sigma, catalog number D8418-1L), DTT (Sigma, catalog number D0632), MgCl ₂ (Sigma, catalog number M1028), 384-well plate ( Labcyte, catalog number P-05525-BC).

Specific experimental methods:

Compound preparation: The test compound was dissolved in DMSO to prepare a 10 mM stock solution. Then, it was diluted 3 times in DMSO medium gradient, and diluted ten times. When adding medicine, dilute it with buffer 10 times.

Ret wt and RET V804M kinase detection: In 5x kinase buffer A, mix Ret wt or RET V804M kinase with pre-diluted compounds of different concentrations for 10 minutes, each concentration in double wells. Add the corresponding substrate and ATP, and react at room temperature for 20 minutes (in which negative and positive controls are set: negative is blank control, and positive is CEP-32496). After the reaction, add the detection reagents (reagents in the HTRF KinEASE-TK kit), and after incubating for 30 minutes at room temperature, use Envision microplate reader to detect the enzyme activity in the presence of the compounds of the present invention at various concentrations, and calculate the compounds of different concentrations For the inhibitory activity of the enzyme activity, according to Graphpad 5.0 software to fit the inhibitory activity of the enzyme activity under different concentrations of compounds, the IC ₅₀ value was calculated, where A means IC ₅₀ ≤10nM, B means 10nM<IC ₅₀ ≤50nM, and C means IC ₅₀ of 50nM <IC ₅₀ ≤100nM, D represents the IC _50> 100nM.

The compounds of the present invention were tested in the above kinase inhibition experiments, and it was found that the compounds of the present invention have potent activity on Ret wt (for example, compounds T-2 to T-4 and T-8 with IC ₅₀ <0.2 nM) and RET V804M. The results of representative example compounds are summarized in Table 1 below.

Table 1:

实施例化合物Example compound	Ret wt IC ₅₀(nM) Ret wt IC ₅₀ (nM)	RET V804M IC ₅₀(nM) RET V804M IC ₅₀ (nM)
T-1T-1	>100>100	75.8075.80
T-2T-2	0.180.18	0.400.40
T-3T-3	0.130.13	0.210.21
T-4T-4	0.160.16	0.280.28
T-5T-5	0.250.25	0.800.80
T-6T-6	0.450.45	1.041.04
T-7T-7	0.150.15	0.200.20
T-8T-8	0.100.10	0.350.35
T-9T-9	0.240.24	0.480.48
T-10T-10	0.100.10	0.230.23
T-11T-11	0.680.68	0.870.87
T-12T-12	0.310.31	1.121.12

Biological Example 2: Cytotoxicity test

(2) Cytotoxicity test

The inhibitory effects of the compounds of the examples on the cell activity of Ba/F ₃ KIF5B-RET and Ba/F ₃ FLT3-ITD were tested.

Consumables and reagents: Fetal Bovine Serum FBS (GIBCO, catalog number 10099141),

Luminescent Cell Viability Assay (Promega, Cat#G7572), 96-well transparent flat-bottomed black wall plate (

Cat#3603).

experimental method:

Cell culture and inoculation:

1. Harvest the cells in the logarithmic growth phase and use a platelet counter to count the cells. Use Trypan blue exclusion method to detect cell viability to ensure that cell viability is above 90%;

2. Adjust the cell concentration to 3000 cells per well; add 90μL of cell suspension to a 96-well plate;

3. Place the cells in the 96-well plate at 37°C, 5% CO ₂ , and 95% humidity for overnight culture.

Drug dilution and dosing:

1. Prepare a 10-fold drug solution, the highest concentration is 10μM, 9 concentrations, 3.16-fold dilution, add 10μL drug solution to each well of the 96-well plate seeded with cells, and set three multiple wells for each drug concentration;

2. Place the cells in the 96-well plate that has been dosing on 37°C, 5% CO ₂ , and 95% humidity for 72 hours, and then perform CTG analysis.

End reading board:

1. Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes;

2. Add an equal volume (10μL) of CTG solution to each well;

3. Vibrate on an orbital shaker for 5 minutes to lyse the cells;

4. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal;

5. Read the luminescence value.

data processing

GraphPad Prism 5.0 software was used to analyze the data, and non-linear S-curve regression was used to fit the data to obtain a dose-response curve, and the IC ₅₀ value was calculated from this. Where A means IC ₅₀ ≤10nM, B means 10nM<IC ₅₀ ≤50nM, C means 50nM<IC ₅₀ ≤100nM, and D means IC ₅₀ >100nM.

Cell survival rate (%)=(Lum test drug-Lum culture solution control)/(Lum cell control-Lum culture solution control)×100%.

The compound of the present invention was tested in the above cytotoxicity experiment, and it was found that the compound of the present invention has potent activity on Ba/F ₃ KIF5B-RET and Ba/F ₃ FLT3-ITD cell lines. The results of representative example compounds are summarized in Table 2 below.

Table 2:

Biological Example 3: Rat pharmacokinetic experiment

Six male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups, 3 rats in each group, and a single dose of the compound (10 mg/kg orally) was administered intravenously or orally, and their pharmacokinetic differences were compared. .

The rats were fed with standard feed and given water. Fasting was started 16 hours before the test. The drug is dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit, and the time points of blood collection were 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration.

The rats were briefly anesthetized after inhaling ether, and a blood sample of 300 μL was collected from the orbit in a test tube. There is 30μL of 1% heparin salt solution in the test tube. Before use, the test tube was dried at 60°C overnight. After the blood samples were collected at the last time point, the rats were anesthetized with ether and sacrificed.

Immediately after the blood sample is collected, gently invert the test tube at least 5 times to ensure sufficient mixing before placing it on ice. The blood sample was centrifuged at 4°C and 5000 rpm for 5 minutes to separate the plasma from the red blood cells. Use a pipette to aspirate 100 μL of plasma into a clean plastic centrifuge tube, and indicate the name and time point of the compound. The plasma is stored at -80°C before analysis. The concentration of the compound of the invention in the plasma was determined by LC-MS/MS. The pharmacokinetic parameters are calculated based on the blood drug concentration of each animal at different time points.

Experiments show that the compound of the present invention has better pharmacokinetic properties in animals, and therefore has better pharmacodynamics and therapeutic effects.

The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as falling within the protection scope of the present invention.

Claims

Compound of formula (I):

among them,

· Ring A and Ring B form an aromatic fused ring;

·A 1 is selected from N atom or C atom, which is optionally substituted by R 1 ;

· A 2 is selected from N atom or C atom, which is optionally substituted by R 2 ;

Wherein each R 1 and R 2 are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-6 alkoxy Group, C 1-6 haloalkoxy or -OC 3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D until fully deuterated;

· A 3 and A 4 are each independently selected from C atom or N atom;

· A 5 and A 6 are each independently selected from N atoms or C atoms, which are optionally substituted by R;

· A 7 and A 8 are each independently selected from N atoms or C atoms, which are optionally substituted by R′;

Wherein R and R'are each independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OC 3-7 cycloalkyl or -L 1 -R a ; wherein the above-mentioned groups are optionally substituted by one or more D until fully deuterated;

Wherein, L 1 is selected from a bond, O, or NH; R a is selected from phenyl or containing 1-3 N, 5 to 6 membered heteromonocyclyl aryl, O or S heteroatoms, wherein said group is optionally substituted with one Or replaced by multiple R b ;

· B 1 , B 2 , B 3 and B 4 are each independently selected from CR * or N;

Wherein each R * is independently selected from H, D, halogen, -CN, -R c , -C (O) R c , -C (O) OR c , -C (O) NR c R d ,- NR c R d , -NR c C(O)R c , -NR c C(O)OR c , -NR c C(O)NR c R d , -OR c , -OC(O)R c ,- OC(O)OR c or -OC(O)NR c R d ;

· L 2 and L 3 are each independently selected from bond, NH, CH 2 , CHD or CD 2 ;

· Ring C is selected from a phenyl group or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms, wherein the group is optionally substituted by one or more R b' ;

Wherein each of R b and R b 'are each independently selected from H, D, -OH, -NH 2 , halogen, -CN, -R c, -C ( O) R c, -C (O) OR c , -C(O)NR c R d , -NR c R d , -NR c C(O)R c , -NR c C(O)OR c , -NR c C(O)NR c R d ,- OR c , -OC(O)R c , -OC(O)OR c or -OC(O)NR c R d , or two R b groups or two R b on the same atom or adjacent atoms ' Groups can be taken together to form a C 3-7 cycloalkyl, a 3 to 7 membered heterocyclic group, a C 6-10 aryl group or a 5 to 10 membered heteroaryl group optionally substituted with one or more R e ;

Each R c and R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group, or R c and Rd together with the N atom to which they are attached form a 3 to 7-membered heterocyclic group or 5 to 10-membered heteroaryl group Group; wherein the group is optionally substituted by one or more R e ;

Each R e is independently selected from H, D, -OH, -NH 2 , halogen, -CN, -R f, -C ( O) R f, -C (O) OR f, -C (O) NR f R g , -NR f R g , -NR f C(O)R f , -NR f C(O)OR f , -NR f C(O)NR f R g , -OR f , -OC( O) R f, -OC (O ) oR f , or -OC (O) NR f R g , or the same atom or two adjacent groups R e on the atom may together form a C 3-7 cycloalkyl group, 3-7 yuan heterocyclyl, C 6-10 aryl group or 5 to 10 membered heteroaryl; wherein each of R e defined group is optionally substituted by one or more D, until fully deuterated;

Each R f and R g is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group, or R f and R g together with the N atom to which they are attached form a 3 to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group Group; wherein each group in the definition of R f and R g is optionally substituted by one or more D until fully deuterated;

Or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
The compound according to claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A 3 and A 4 are One C atom and one N atom.
The compound according to claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A 5 , A 6 At least one of and A 7 is a N atom.
The compound according to any one of claims 1 to 3, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A One of 7 and A 8 is replaced by -L 1 -R a .
The compound according to any one of claims 1 to 4, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A 1 is a C atom, and A 2 is a N atom.
The compound according to any one of claims 1-5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R a is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or iso Thiazolyl; wherein the group is optionally substituted with one or more R b .
The compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L 2 is selected from bond, CH 2 , CHD or CD 2 .
The compound according to any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Ring C is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or iso Thiazolyl; wherein the group is optionally substituted with one or more R b' .
The compound according to any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Ring C is selected from 5 to 6 membered heteroaryl groups containing 1-3 N, O, or S heteroatoms, wherein the group is optionally substituted with one or more R b' .
The compound according to any one of claims 1-9, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The compound has the following general structure:

among them,

W 1 and V 1 are each independently selected from CR b or N;

W 2 and V 2 are each independently selected from CR b 'or N;

Other parameters are as defined in any one of claims 1-9.
The compound according to any one of claims 1-10, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The compound is the following formula:

A 3 and A 4 are each independently selected from C atom or N atom, and there is one C atom and one N atom;

A 5 and A 6 are each independently selected from N atoms or C atoms, which are optionally substituted by R;

A 7 and A 8 are each independently selected from N atom or C atom, which is optionally substituted by R′;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R'is independently selected from H, D, halogen, -CN or -L 1 -R a ;

One of A 7 and A 8 is replaced by -L 1 -R a ;

Wherein, L 1 is selected from a bond, O, or NH; R a is
Where * indicates the connection position with L 1 ;

B 1 and B 2 are each independently selected from CR * or N;

Wherein each R * is independently selected from H, D, halogen or -CN;

Or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The compound is the following formula:

among them,

A 5 and A 6 are each independently selected from N atoms or C atoms, which are optionally substituted by R;

A 7 and A 8 are each independently selected from N atom or C atom, which is optionally substituted by R′;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R'is independently selected from H, D, halogen, -CN or -L 1 -R a ;

And at least one of A 5 , A 6 and A 7 is N, and one of A 7 and A 8 is substituted by -L 1 -R a ;

Wherein, L 1 is selected from a bond, O, or NH; R a is
Where * indicates the connection position with L 1 ;

B 1 and B 2 are each independently selected from CR * or N;

Wherein each R * is independently selected from H, D, halogen or -CN;

Or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
The compound according to any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The compound is the following formula:

among them,

A 5 and A 6 are each independently selected from N atoms or C atoms, which are optionally substituted by R;

A 7 is selected from N atom or C atom, which is optionally substituted by R';

And at least one of A 5 , A 6 and A 7 is N;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R'is independently selected from H, D, halogen or -CN;

Or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
The compound according to any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The compound is the following formula:

among them,

A 5 and A 6 are each independently selected from N atoms or C atoms, which are optionally substituted by R, and at least one of them is a N atom;

B 1 and B 2 are each independently selected from CR * or N;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R * is independently selected from H, D, halogen or -CN;

Preferably, B 1 and B 2 are both CR * ;

Or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The compound is the following formula:

among them,

A 5 and A 6 are each independently selected from N atoms or C atoms, which are optionally substituted by R;

A 8 is selected from N atom or C atom, which is optionally substituted by R′;

B 1 and B 2 are each independently selected from CR * or N;

Wherein each R is independently selected from H, D, halogen or -CN;

Each R * is independently selected from H, D, halogen or -CN;

Preferably, at least one of A 5 , A 6 and A 8 is a N atom; more preferably A 5 is a N atom;

Or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
The compound or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein the compound is selected from:
A pharmaceutical composition containing the compound of any one of claims 1-16 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, And pharmaceutically acceptable excipients.
The compound of any one of claims 1-16 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 17 Use of the composition in the preparation of a medicine for treating and/or preventing diseases.
The compound of any one of claims 1-16 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 17 Compositions for the treatment and/or prevention of diseases.
A method for treating and/or preventing a disease in a subject, comprising administering to the patient the compound of any one of claims 1-16 or a tautomer, stereoisomer, prodrug, Crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of claim 17.
The use according to claim 18 or the compound or pharmaceutical composition according to claim 19 or the method according to claim 20, wherein the disease is a protein kinase-mediated disease, for example selected from RET, KIF5B-RET , CCDC6-RET, Trk, FLT3, c-Kit, PDGFR or VEGFR kinase wild-type and mutants of one or more kinase-mediated diseases.
The use or compound or pharmaceutical composition or method according to claim 21, wherein the mutants of RET, KIF5B-RET and CCDC6-RET kinase are selected from the group consisting of V804L, V804M, V804E, M918T, E805K, Y806C, Y806E , C634Y or C634W.
The use or compound or pharmaceutical composition or method according to claim 21, wherein the Trk kinase mutant is selected from G595R.
The use or compound or pharmaceutical composition or method according to claim 21, wherein the FLT3 kinase mutant is selected from F691L, D835Y, D835V, D835H, D835F, D835E, Y842C, Y842D, Y842H, Y842N, Y842S Or FLT3-ITD.
The use of claim 18 or the compound or pharmaceutical composition of claim 19 or the method of claim 20, wherein the disease is selected from the group consisting of non-small cell lung cancer, papillary thyroid cancer, pleomorphic adult Glioma, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine carcinoma, prostate cancer, colon cancer, acute lymphoblastic leukemia, sarcoma, pediatric glioma, intrahepatic cholangiocarcinoma, hairy cell carcinoma Astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland carcinoma, secretory breast cancer, fibrosarcoma, nephroma, breast cancer, myelodysplastic syndrome, gastrointestinal stromal tumor, melanoma, sperm Primary cell tumor, intracranial germ cell tumor, mediastinal B-cell lymphoma.